A sequential two-component etherification/oxa-conjugate addition reaction: Asymmetric synthesis of (+)-leucascandrolide A macrolactone

Article abstract of DOI:10.1002/anie.200801357

A smooth operator: The asymmetric synthesis of the macrolactone of (+)-leucascandrolide A (see structure) has been accomplished through a convergent route (longest linear sequence of 14 steps) in 20% overall yield. The assembly of the 1,5-bis(tetrahydropyran) core in a single operation provides the most concise synthetic approach developed to date. (Chemical Equation Presented)

Full text of DOI:10.1002/anie.200801357

Communications
DOI: 10.1002/anie.200801357
Natural Product Synthesis
A Sequential Two-Component Etherification/Oxa-Conjugate Addition
Reaction: Asymmetric Synthesis of (+)-Leucascandrolide A
Macrolactone **
P. Andrew Evans* and William J. Andrews
Dedicated to Professor Andrew B. Holmes on the occasion of his 65th birthday
Leucascandrolide A (1) is a novel macrolide possessing an
unusual dioxotricyclic core, which displays potent cytotoxic
speculation with respect to the actual source of this agent,
which has tentatively been attributed to opportunistic bac-
teria colonizing a decayed portion of the sponge rather than a
more classical symbiotic relationship.Hence, the unique
molecular architecture and potent biological activity, coupled
with the lack of bioavailability from natural sources, have
inspired several outstanding syntheses of this important
target.[3,4] Although these approaches have significant merit,
both in terms of their strategic and methodological develop-
ments, they each construct the key 1,5-bis(tetrahydropyran)
moiety in a stepwise manner.
Herein, we describe the most concise approach to
leucascandrolide A (1) developed to date, by using a novel
two-component etherification/oxa-conjugate addition reac-
tion.It is anticipated that this strategy should be easily
adapted to prepare related analogues of this important agent,
which may provide insight into its mode of action.We
envisioned the construction of the leucascandrolide A macro-
lactone (2) could be accomplished through macrolactoniza-
tion of the seco acid 3 followed by removal of the benzyl
group in an analogous manner to that described in a related
approach (Scheme 1).[3] The seco acid 3 would be prepared
from 4 through the stereoselective introduction of the alkenyl
group to the aldehyde derived from the terminal alkene, and
the reduction of the C9 ketone followed by methylation of the
secondary alcohol.The 1,5-bis(tetrahydropyran) 4 would in
turn be derived from reaction of the anomeric acetal 5 with
the trimethylsilyloxy diene 6 via a one-pot diastereoselective
sequential two-component etherification, followed by an oxa-
conjugate addition.The anomeric acetal 5 and trimethylsilyl-
oxy diene 6 required for the coupling would be readily
available from the known enantiomeric b-hydroxy esters (R)-
and (S)-7, respectively.
activity against KB (throat epithelial cancer, IC50
=
0.05 mgmLꢀ1) and P388 (murine leukemia, IC50
=
0.25 mgmLꢀ1) tumor cell lines, in addition to antifungal
activity against Candida albicans.[1] The latter feature is
particularly important given the growing concern among
AIDS patients with regard to infections from this animal-
pathogenic yeast.Interestingly, the cytotoxic activity of 1 can
primarily be attributed to the macrolide moiety, whereas the
antifungal activity derives from the oxazole side chain.Hence,
the ability to construct this agent in a more expeditious
manner would provide the opportunity to conduct more
detailed structure–activity studies and potentially capitalize
on this divergent behavior.Although this agent was originally
isolated from the calcareous sponge Leucascandra caveolata
in the Coral Sea by Pietra and co-workers,[2] subsequent
attempts to isolate the material have failed.This has led to
[*] Prof. Dr. P. A. Evans
Department of Chemistry
The University of Liverpool
Liverpool, L69 7ZD (UK)
In a program directed towards the stereoselective con-
struction of monocyclic ethers, we have developed a series of
bismuth-mediated reactions for the construction of cis- and
trans-2,6-disubstituted tetrahydropyrans.[5] A striking feature
of this methodology has been the ability to develop multi-
component etherification reactions, by using the rate of
desilylation to orchestrate the cascade process.However, a
critical requirement for the application of this strategy to the
construction of the 1,5-bis(tetrahydropyran) core of leucas-
candrolide A is the ability to circumvent reversibility in the
oxa-conjugate addition process so as to avoid complications
with the epimerization of the trans-2,6-disubstituted tetrahy-
dropyran ring.Although base-catalyzed variations are known
Fax: (+44)151-794-1377
E-mail: andrew.evans@liverpool.ac.uk
Homepage: http://osxs.ch.liv.ac.uk/
W. J. Andrews
Department of Chemistry
Indiana University
Bloomington, IN 47405 (USA)
[**] We sincerely thank the National Institutes of Health (GM54623) for
generous financial support. We also thank the Royal Society for a
Wolfson Research Merit Award (P.A.E.). We also acknowledge Daiso
Chemical Co. Ltd. for the generous and kind gift of (R)- and (S)-
ethyl-4-chloro-3-hydroxybutyrate.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200801357.
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The synthesis of the anomeric acetate 5, required for the
left-hand fragment of leucascandrolide A, commenced from
the known homoallylic alcohol (R)-7.[6] This is readily
available from the regiospecific ring opening of commercially
available ethyl (S)-oxiranyl acetate with the cuprate derived
from vinylmagnesium bromide and copper bromide-dimethyl
sulfide complex in 88% yield.[7] The hydroxy group of (R)-7
was protected as a triisopropylsilyl ether, then reduced with
diisobutylaluminum hydride, and the primary alcohol con-
verted into the primary alkyl iodide 11 in 90% overall yield
[8]
(Scheme 2).Asymmetric alkylation
of (1R,2R)-(ꢀ)-pseu-
Scheme 2. Synthesis of the anomeric acetate 5: a) TIPSOTf, imidazole,
DMF, 08C!RT, 96%; b) DIBAL-H, CH2Cl2, ꢀ40!ꢀ208C , 99%; c) I,
2
PPh3, imidazole, CH2Cl2, 08C!RT, 95%; d) (1R, 2R)-pseudoephedrine
propionamide, LDA, LiCl, THF, ꢀ78!08C, 8; then TBAF, PTSA,
ꢀ108C!RT, 72%; e) DIBAL-H, CH2Cl2, ꢀ788C , AcO, pyridine, DMAP,
2
88%. DIBAL-H=diisobutylaluminum hydride, DMAP=4-dimethylami-
nopyridine, DMF=N,N-dimethylformamide, LDA=lithium diisopropyl-
amide, PTSA=para-toluenesulfonic acid, TBAF=tetrabutylammonium
fluoride, Tf=triflate, TIPS=triisopropylsilyl.
doephedrine propionamide with 11 according to the proce-
dure developed by Myers et al.was followed by in situ
removal of the triisopropylsilyl group and acid-catalyzed
lactonization to afford d-lactone 12 in 72% yield and with
Scheme 1. Retrosynthetic analysis for (+)-leucascandrolide A macro-
lactone (2). Bn=benzyl, TBS=tert-butyldimethylsilyl, TMS=trimethyl-
silyl.
1
excellent diastereoselectivity (d.s. ꢁ 19:1, by H NMR spec-
to proceed under thermodynamic control, we have recently
demonstrated that the Brønsted acid catalyzed variation,
using Bi(NO3)3·5H2O as the acid source, minimizes revers-
ibility making this approach now viable.Preliminary studies
demonstrated the necessity for a dual Lewis and Brønsted
acid catalyzed process to affect this type of sequential process.
Treatment of the anomeric acetate 8 with the diene 9
(1.5 equiv) in the presence of BF3·OEt2 at ꢀ408C followed
by the addition of a catalytic amount of Bi(NO3)3·5H2O and
warming to 08C furnished the non-adjacent bis(tetrahydro-
pyran) core 10 [Eq.(1)] in 65% yield with ꢁ 19:1 diastereo-
selectivity (by 1H NMR spectroscopy).Additional support for
the necessity of a Brønsted acid catalyzed oxa-conjugative
addition was evident from the fact that the simple model
system 10 undergoes base-catalyzed equilibration at C11.
troscopy).[9] Reduction of 12 with diisobutylaluminum hy-
dride followed by in situ acylation of the lactol with acetic
anhydride furnished anomeric acetate 5 in 88% yield as a
mixture of anomers (a/b = 5:1, by 1H NMR spectroscopy).[10]
Scheme 3 outlines the synthesis of the trimethylsilyloxy
diene 6, which commenced with benzyl protection of the
enantiomeric b-hydroxy ester (S)-7, followed by selective
reduction of the ester to give aldehyde 13 required for the
Scheme 3. Synthesis of the trimethylsilyloxy diene 6: a) PhCH2Br,
Ag2O, EtOAc, 89%; b) DIBAL-H, CH2Cl2, ꢀ788C , 94%; c)N-Ts-l-
=
valine, BH3·THF, PhO(TMSO)C CH2, THF, ꢀ788C, 87%; d) TBSOTf,
imidazole, DMF, 08C!RT, 99%; e) Hoveyda–Grubbs catalyst
=
(5 mol%), CH2 CHCOMe, (5 equiv), CH2Cl2, RT, 93%; f) TMSOTf,
Et3N, THF, ꢀ788C!RT, 99%. Ts=para-toluenesulfonyl.
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Communications
asymmetric Mukaiyama aldol.[11] Treatment of the aldehyde
13 with the trimethylsilyl enol ether of phenyl acetate and
N-tosyl-l-valine boron Lewis acid gave the corresponding
b-hydroxy ester (d.s. = 15:1, by 1H NMR spectroscopy), which
was then protected to furnish the tert-butyldimethylsilyl ether
14 in 82% overall yield.The fragment was then completed by
the conversion of the terminal olefin to the a,b-unsaturated
ketone via a cross-metathesis reaction with methyl vinyl
ketone,[12] followed by treatment with trimethylsilyl triflate
and triethylamine to afford the trimethylsilyloxy diene 6 in
92% overall yield (Scheme 3).
The successful completion of the individual fragments
provided an opportunity to examine the key one-pot diaste-
reoselective sequential two-component etherification/oxa-
conjugate addition reaction for the construction of the non-
adjacent bis(tetrahydropyran) core of the natural product
Scheme 4. Completion of the total synthesis of (+)-leucascandrolide A
[Eq.(2)]. Gratifyingly, treatment of the anomeric acetate
5
macrolactone (2): a) O3, NaHCO3, C HCl2, ꢀ788C, then DMS, PPh3,
2
with the diene 6 (1.5 equiv), in an analogous manner to that of
the model study [Eq.(1)], furnished the non-adjacent bis(tet-
rahydropyran) core 4 in an improved 78% yield, with
ꢂ
ꢀ788C!RT; b) iBuC CH, [Cp2ZrHCl], CH2Cl2, ꢀ788C; then (ꢀ)-MIB,
ꢀ108C, 75% (over 2 steps); c) Ac2O, pyridine, DMAP, CH2Cl2, 08C!
RT, 91%; d) catecholborane, (S)-CBS, CH2Cl2, ꢀ788C; e) MeOTf, 2,6-
di-tert-butylpyridine, RT; then LiOH·H2O, H2O, MeOH, THF, RT, 85%
(over 2 steps); f) Cl3C6H2COCl, Et3N, DMAP, PhH, RT, 81%; g) DDQ
(20 equiv), pH buffer, CH2Cl2, RT, 88%. Cp=cyclopentadienyl,
DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, DMS=dimethyl
sulfide, (S)-CBS=(S)-methyl oxazaborolidine, MIB=morpholino iso-
borneol.
1
excellent diastereoselectivity (d.s. ꢁ 19:1, by H NMR spec-
troscopy).[5]
lide A macrolactone (2) in 71% overall yield, thus completing
our formal total synthesis of the natural product (see the
Supporting Information).The spectroscopic data and optical
rotation of (+)-leucascandrolide A macrolactone 2 was
identical in all respects to the values reported in the literature
[1H/13C NMR, IR, [a]D24 + 46.2 (c = 0.39, EtOH), lit.[1] [a]D20
+ 58 (c = 0.1, EtOH)]. (+)-Leucascandrolide A (1) has pre-
viously been prepared from 2 by the introduction of the side
chain through a Mitsunobu esterification at C5 in 78%
yield.[3b]
Scheme 4 outlines the completion of the (+)-leucascan-
drolide A macrolactone (2).Although the introduction of the
alkenyl side chain initially proved problematic, a combination
of the procedures developed by the research groups of Wipf
and Walsh provided suitable reaction conditions for its
installation.[13] Hence, ozonolysis of the terminal alkene of 4
gave the corresponding aldehyde, followed by treatment with
the organozinc reagent derived from the hydrozirconation of
4-methylpentyne, in the presence of the (ꢀ)-MIB ligand,
furnished the allylic alcohol 15 in 75% yield over two steps,
after separation from the epimer (d.s. = 6:1, by 1H NMR
spectroscopy; Scheme 4).[14] Protection of the secondary
alcohol of 15 with an acetate group followed by reduction[15]
of the ketone afforded the desired alcohol with excellent
selectivity (d.s. ꢁ 19:1, by 1H NMR spectroscopy).Methy-
lation of the resulting secondary alcohol followed by in situ
saponification of both the acetate and the phenyl ester
provided seco acid 3 in 77% yield (over 3 steps).The seco
acid 3 was converted into the macrolide using relatively
standard transformations in accord with prior studies.[3]
Yamaguchi macrolactonization[16] of the seco acid 3 followed
by removal of the benzyl group furnished (+)-leucascandro-
In conclusion, we have accomplished the asymmetric
synthesis of (+)-leucascandrolide A macrolactone (2) by
using a convergent 14-step sequence from the known
(S)-b-hydroxy ester 7 in 20% overall yield, or 15 steps from
the commercially available ethyl (R)-oxiranyl acetate in 18%
overall yield.The combination of the two-component ether-
ification and oxa-conjugate addition reactions provides the
most convergent and efficient approach to the non-adjacent
tetrahydrofuran core and ultimately leucascandrolide A (1)
developed to date.We anticipate that this strategy will
facilitate structure–activity relationship studies to further
delineate the intriguing dichotomy in biological activity.
Received: March 20, 2008
Published online: June 13, 2008
Keywords: antifungal agents · asymmetric synthesis ·
.
cytotoxicity · natural products · total synthesis
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